Ceruloplasmin (Cp) is a ferroxidase enzyme that is essential for cell iron efflux and has been postulated to have a neuroprotective role. During the myelination process, oligodendrocytes (OLs) and Schwann cells (SCs) express high levels of Cp, but the role of this enzyme in glial cell development and function is completely unknown. To define the function of Cp in the myelination of the central and peripheral nervous systems, we have conditionally knocked-out Cp specifically in OLs and SCs during early postnatal development as well as in aged mice. Cp ablation in early OLs (postnatal day 2, P2) significantly affects the differentiation of these cells and the synthesis of myelin through the first four postnatal weeks. The total number of mature myelinating OLs was reduced, and the density of apoptotic OLs was increased. These changes were accompanied with reductions in the percentage of myelinated axons and increases in the g-ratio of myelinated fibers. Cp ablation in young myelinating OLs (P30 or P60) did not affect myelin synthesis and/or OL numbers, however, Cp loss in aged OLs (8 months) induced cell iron overload, apoptotic cell death, brain oxidative stress, neurodegeneration and myelin disruption. Furthermore, Cp deletion in SCs affected postnatal SC development and myelination and produced motor coordination deficits as well as oxidative stress in young and aged peripheral nerves. Together, our data indicate that Cp ferroxidase activity is essential for OLs and SCs maturation during early postnatal development and iron homeostasis in matured myelinating cells. Additionally, our results suggest that Cp expression in myelinating glial cells is crucial to prevent oxidative stress and neurodegeneration in the central and peripheral nervous systems.

血浆铜蓝蛋白 ( Cp ) 是一种亚铁氧化酶，对细胞铁外流至关重要，并被假定具有神经保护作用。在髓鞘形成过程中，少突胶质细胞 ( OLs ) 和雪旺细胞 ( SCs)) 表达高水平的 Cp，但这种酶在神经胶质细胞发育和功能中的作用是完全未知的。为了确定 Cp 在中枢和外周神经系统髓鞘形成中的功能，我们在出生后早期发育以及老年小鼠中，有条件地敲除 OL 和 SCs 中的 Cp。早期 OL（出生后第 2 天，P2）中的 Cp 消融显着影响这些细胞的分化和出生后前四个星期的髓鞘合成。成熟有髓鞘OLs总数减少，凋亡OLs密度增加。这些变化伴随着有髓轴突百分比的减少和g- 有髓纤维的比例。年轻有髓鞘的 OL（P30 或 P60）中的 Cp 消融不影响髓鞘合成和/或 OL 数量，但是，老年 OL（8 个月）的 Cp 损失会诱导细胞铁过载、细胞凋亡、脑氧化应激、神经变性和髓鞘破坏. 此外，SCs 中的 Cp 缺失影响出生后 SC 发育和髓鞘形成，并在年轻和年老的周围神经中产生运动协调缺陷以及氧化应激。总之，我们的数据表明，Cp 亚铁氧化物酶活性对于出生后早期发育过程中的 OL 和 SCs 成熟以及成熟髓鞘细胞中的铁稳态至关重要。此外，我们的结果表明，髓鞘胶质细胞中的 Cp 表达对于防止中枢和外周神经系统中的氧化应激和神经变性至关重要。